- Conjugation with Phenylalanine Enhances Autophagy-Inducing Activity of (-)-Epigallocatechin Gallate (EGCG) in Hepatic Cells. [Journal Article]
- JAJ Agric Food Chem 2018 Nov 12
- Given the importance of (-)-epigallocatechin gallate (EGCG) as an autophagy-enhancing and thereby lipid-lowering agent, optimization of its activity warrants its therapeutic potential in the treatmen...
Given the importance of (-)-epigallocatechin gallate (EGCG) as an autophagy-enhancing and thereby lipid-lowering agent, optimization of its activity warrants its therapeutic potential in the treatment of hepatic diseases as well as metabolic disorders. Based on our previous observations that structural modifications provided substantial improvements in the bioactivity of EGCG, we investigated the autophagy-enhancing activity of EGCG derivatives. Among 14 EGCG derivatives, E10 with a phenylalanine attached to the D-ring of the EGCG exhibited the most promising effects in stimulating autophagy in Huh7 cells, which was supported by several lines of evidence: 1) stimulation of autophagy revealed by an increased amount of LC3B-II (4.1±0.8-fold compared to the control) as well as the 2.0±0.1-folds activation of AMPK (AMP-activated protein kinase) in the presence of E10; 2) E10-stimulated autophagic flux demonstrated by a 1.6±0.4-fold increase in LC3B-II upon co-treatment with chloroquine (CQ), 38.1±5.6% reduction of p62/SQSTM1, and an increase in the formation of autophagic compartments visualized by both CYTO-ID staining (3.0±0.1-fold) and tandem RFP-GFP-LC3 fluorescence (2.7±0.4-fold and 3.2±0.3-fold for green and red fluorescence, respectively). Finally, the autophagy-inducing activity of E10 culminated in a 5.3-fold reduction of hepatic lipid accumulation caused by fatty acids. In all of the assay settings, E10 was consistently 1.3 to 3.5-fold more potent than EGCG. Taken together, we demonstrated a significant increase in autophagy stimulating activity of EGCG through structural modifications.
- Risk of Ocular Anomalies in Children Exposed in Utero to Antimalarials: A Systematic Literature Review. [Journal Article]
- ACArthritis Care Res (Hoboken) 2018 Nov 12
- CONCLUSIONS: In children exposed to appropriate doses of antimalarials antenatally, the risk of ocular toxicity appears low to nonexistent. The potential benefits and risks of antimalarials should be discussed in all SLE pregnancies, and high dosages should continue to be avoided. This article is protected by copyright. All rights reserved.
- Chloroquine inhibits human retina pigmented epithelial cell growth and microtubule nucleation by downregulating p150glued. [Journal Article]
- JCJ Cell Physiol 2018 Nov 11
- Chloroquine (CQ) is an antimalaria drug that has been used in clinical practice for several decades. One serious complication of CQ treatment is the macular retinopathy caused by the disruption of th...
Chloroquine (CQ) is an antimalaria drug that has been used in clinical practice for several decades. One serious complication of CQ treatment is the macular retinopathy caused by the disruption of the retinal pigmented epithelium, leading to vision loss. Little is known about how CQ affects retinal pigmented epithelium. In this study, we found that cell proliferation was reduced by CQ treatment in time and dose-dependent manners. No obvious cell death was detected; however, what was observed instead was G0/G1 arrest during which primary cilium started to grow in the presence of CQ. Pharmacological inhibition of primary cilium formation led to a reduction of cell viability suggesting that CQ-induced primary cilium protected cells from death. In addition to cell growth, with the CQ treatment the retina pigmented epithelium (RPE) cells less flattened with the spindle-like protrusion. When checking the microtubule networks, the microtubule nucleation activity was disrupted in the presence of CQ. The level of p150 glued , the largest subunit of dynactin, was reduced in CQ-treated RPE1 cells, and depletion of p150 glued resulted in a phenotype reminiscent of CQ-treated cells. Thus, CQ treatment reduced the expression of p150 glued , leading to reduced S phase entry and defective microtubule nucleation.
- TFEB protects nucleus pulposus cells against apoptosis and senescence via restoring autophagic flux. [Journal Article]
- OCOsteoarthritis Cartilage 2018 Nov 08
- CONCLUSIONS: Experimental IVDD inhibited the TFEB activity. TFEB overexpression suppressed TBHP-induced apoptosis and senescence via autophagic flux stimulation in NP cell and alleviates puncture-induced IVDD development in vivo.
- Continuous removal of the model pharmaceutical chloroquine from water using melanin-covered Escherichia coli in a membrane bioreactor. [Journal Article]
- JHJ Hazard Mater 2018 Oct 29; 365:74-80
- Environmental release and accumulation of pharmaceuticals and personal care products is a global concern in view of increased awareness of ecotoxicological effects. Adsorbent properties make the biop...
Environmental release and accumulation of pharmaceuticals and personal care products is a global concern in view of increased awareness of ecotoxicological effects. Adsorbent properties make the biopolymer melanin an interesting alternative to remove micropollutants from water. Recently, tyrosinase-surface-displaying Escherichia coli was shown to be an interesting self-replicating production system for melanin-covered cells for batch-wise absorption of the model pharmaceutical chloroquine. This work explores the suitability of these melanin-covered E. coli for the continuous removal of pharmaceuticals from wastewater. A continuous-flow membrane bioreactor containing melanized E. coli cells was used for adsorption of chloroquine from the influent until saturation and subsequent regeneration. At a low loading of cells (10 g/L) and high influent concentration of chloroquine (0.1 mM), chloroquine adsorbed until saturation after 26 ± 2 treated reactor volumes (39 ± 3 L). The average effluent concentration during the first 20 h was 0.0018 mM, corresponding to 98.2% removal. Up to 140 ± 6 mg chloroquine bound per gram of cells following mixed homo- and heterogeneous adsorption kinetics. In situ low-pH regeneration released all chloroquine without apparent capacity loss over three consecutive cycles. This shows the potential of melanized cells for treatment of conventional wastewater or highly concentrated upstream sources such as hospitals or manufacturing sites.
- Benzene induces haematotoxicity by promoting deacetylation and autophagy. [Journal Article]
- JCJ Cell Mol Med 2018 Nov 08
- Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, es...
Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene-induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.
- Hydroxychloroquine-induced autophagic vacuolar myopathy with mitochondrial abnormalities. [Case Reports]
- NNeuropathology 2018 Nov 08
- Hydroxychloroquine (HCQ) and chloroquine are used worldwide for malaria as well as connective and rheumatological disorders. They have been reported to be linked to myopathy in patients. We report fo...
Hydroxychloroquine (HCQ) and chloroquine are used worldwide for malaria as well as connective and rheumatological disorders. They have been reported to be linked to myopathy in patients. We report four patients who were receiving HCQ as part of treatment for connective tissue disorder and who presented with myopathy. The muscle biopsy in these patients was consistent with findings of HCQ toxicity. HCQ muscle toxicity is usually self-limiting after discontinuation of the drug. It also usually tends to be under-reported due to presence of various confounding factors. This warrants close monitoring and consideration of muscle biopsy as part of initial work up of patients who present with myopathy while receiving HCQ.
- Lysosome membrane permeabilization and disruption of mTOR-lysosome interaction are associated with the inhibition of lung cancer cell proliferation by a chloroquinoline analog. [Journal Article]
- MPMol Pharmacol 2018 Nov 08
- Lysosomes degrade cellular proteins and organelles, and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably mTORC1. The striking differences in the...
Lysosomes degrade cellular proteins and organelles, and regulate cell signaling by providing a surface for the formation of critical protein complexes, notably mTORC1. The striking differences in the lysosomes of cancer versus normal cells suggest that the lysosome would be a target for drug development. While the lysomotropic drugs chloroquine (CQ) and hydroxychloroquine (HCQ) have been widely investigated, studies have focused on their ability to inhibit autophagy. We synthesized a novel compound, named EAD1, that is structurally related to CQ but is 14-fold more potent. Here we find that EAD1 causes rapid lysosome relocation, lysosome membrane permeabilization (LMP), and lysosome deacidification, induces apoptosis, and irreversibly blocks lung cancer cell proliferation. EAD1 also potently causes the dissociation of mTOR from lysosomes and increases mTOR's perinuclear vs cytoplasmic localization, changes previously shown to inactivate mTORC1. The effect on mTOR was not seen with HCQ, even at >10-fold higher concentrations. Phosphorylation of a downstream target of mTORC1, ribosomal protein S6, was inhibited by EAD1. Although EAD1 also inhibited autophagy, it strikingly retained full antiproliferative activity in autophagy-deficient H1650 lung cancer cells, which have a biallelic deletion within the Atg7 locus, and in H460 Atg7-knockout cells. As Atg7 is critical for the canonical autophagy pathway, it is likely that inhibition of autophagy is not how EAD1 inhibits cell proliferation. Further studies are needed to determine the relationship of LMP to mTORC1 disruption, and their relative contributions to drug-induced cell death. These studies support the lysosome as an underexplored target for new drug development.
- Assessment of drug resistance associated genetic diversity in Mauritanian isolates of Plasmodium vivax reveals limited polymorphism. [Journal Article]
- MJMalar J 2018 Nov 08; 17(1):416
- CONCLUSIONS: Polymorphisms in Pvdhfr, Pvdhps, Pvmdr1, and Pvk12 were limited in P. vivax isolates collected recently in Nouakchott and Atar. Compared to the isolates collected in Nouakchott in 2007-2009, there was no evidence for selection of mutants. The presence of one, but not both, of the two potential markers of chloroquine resistance in Pvmdr1 in pre-treatment isolates did not influence the clinical outcome, putting into question the role of Pvmdr1 mutant alleles 976F and 1076L in treatment failure. Molecular surveillance is an important component of P. vivax malaria control programme in the Saharan zone of Mauritania to predict possible emergence of drug-resistant parasites.
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- Second generation of diazachrysenes: Protection of Ebola virus infected mice and mechanism of action. [Journal Article]
- EJEur J Med Chem 2018 Oct 31; 162:32-50
- Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design,...
Ebola virus (EBOV) causes a deadly hemorrhagic fever in humans and non-human primates. There is currently no FDA-approved vaccine or medication to counter this disease. Here, we report on the design, synthesis and anti-viral activities of two classes of compounds which show high potency against EBOV in both in vitro cell culture assays and in vivo mouse models Ebola viral disease. These compounds incorporate the structural features of cationic amphiphilic drugs (CAD), i.e they possess both a hydrophobic domain and a hydrophilic domain consisting of an ionizable amine functional group. These structural features enable easily diffusion into cells but once inside an acidic compartment their amine groups became protonated, ionized and remain trapped inside the acidic compartments such as late endosomes and lysosomes. These compounds, by virtue of their lysomotrophic functions, blocked EBOV entry. However, unlike other drugs containing a CAD moiety including chloroquine and amodiaquine, compounds reported in this study display faster kinetics of accumulation in the lysosomes, robust expansion of late endosome/lysosomes, relatively more potent suppression of lysosome fusion with other vesicular compartments and inhibition of cathepsins activities, all of which play a vital role in anti-EBOV activity. Furthermore, the diazachrysene 2 (ZSML08) that showed most potent activity against EBOV in in vitro cell culture assays also showed significant survival benefit with 100% protection in mouse models of Ebola virus disease, at a low dose of 10 mg/kg/day. Lastly, toxicity studies in vivo using zebrafish models suggest no developmental defects or toxicity associated with these compounds. Overall, these studies describe two new pharmacophores that by virtue of being potent lysosomotrophs, display potent anti-EBOV activities both in vitro and in vivo animal models of EBOV disease.